Potentiating Adoptive T Cell Therapy by Immunomodulation

描述(由申请人提供)：包括体外分离和扩增抗原特异性T细胞的过继治疗产生了以最小的毒性消除肿瘤和免疫保护的前景。近年来，这种方法在治疗转移性黑色素瘤患者方面取得了有希望的结果。然而，转移的T细胞在体内的存活和功能以及最终导致患者肿瘤消退的因素还有待定义和优化。人们认为输注前的调节和输注后细胞因子的应用有助于过继转移T细胞的疗效。我们推测，使用确定数量、表型和特异性的T细胞克隆进行过继治疗将允许对免疫调节方案的影响进行精确和严格的检查，并有助于识别导致策略成功的因素。我们建议在I期剂量发现研究中，确定输注前的环磷酰胺调节方案和输注后的IL-2剂量，该剂量是安全的，并支持过继转移的T细胞在体内的存活和功能。将在第一阶段研究中实施的环磷酰胺的剂量范围为300至4000毫克/平方米，这是基于先前的临床试验，证明了环磷酰胺的免疫增强作用。输注后低剂量和高剂量IL-2的剂量和时间已经在先前的过继T细胞治疗影响体内T细胞存活的临床试验中被牵连。在这项最初的第一阶段研究中确定的环磷酰胺调节方案和输注后IL-2计划被认为是安全的，并最大限度地提高T细胞的持久性，将在扩展的第二阶段研究中评估临床疗效。公共卫生研究(通俗语言)：对标准化疗和放射耐药的癌症可能可以使用免疫系统的组件进行治疗。我们建议使用免疫细胞，即T细胞，识别肿瘤细胞上的靶点，作为治疗晚期(转移性)黑色素瘤患者的一种手段。通过分离和扩增这种T细胞并将它们注入患者体内，我们可以跟踪这些细胞的生存和功能，并希望找到一种安全的治疗方法，将提高黑色素瘤特异性T细胞的有效性。

DESCRIPTION (provided by applicant): Adoptive therapy involving the ex vivo isolation and expansion of antigen-specific T cells yields the promise of tumor eradication and immunoprotection with minimal toxicity. In recent years, this modality has produced promising results for the treatment of patients with metastatic melanoma. However, factors contributing to the in vivo survival and function of transferred T cells and ultimately, tumor regression in patients, have yet to be defined and optimized. It is believed that pre-infusion conditioning and post-infusion cytokine administration contribute to the efficacy of adoptively transferred T cells. We postulate that the use of T cell clones of defined magnitude, phenotype and specificity for adoptive therapy will permit a precise and rigorous examination of the influence of immunomodulatory regimens and facilitate the identification of elements responsible for a successful strategy. We propose to identify in a Phase I, dose-finding study, a cyclophosphamide conditioning regimen pre- infusion and a dose of IL-2 post-infusion that is safe and that supports the in vivo survival and function of adoptively transferred T cells. The dosing range for cyclophosphamide that will be implemented in the Phase I study, 300 to 4,000 mg/m2, is grounded in previous clinical trials demonstrating an immunopotentiating effect of cyclophosphamide. The dose and schedule of post-infusion low-dose and high-dose IL-2 have been implicated in previous clinical trials of adoptive T cell therapy to impact T cell survival in vivo. A cyclophosphamide conditioning regimen and post-infusion IL-2 schedule identified in this initial Phase I study that is deemed to be safe and that maximizes T cell persistence will be evaluated for clinical efficacy in an extended Phase II study. of Research to Public Health (lay language): Cancers that are resistant to standard chemotherapy and radiation may be treatable using components of the immune system. We propose to use immune cells, T cells, that recognize targets on tumor cells as a means of treating patients with advanced (metastatic) melanoma. By isolating and expanding such T cells and infusing them into patients, we can track the survival and function of these cells and, we hope, identify a treatment approach that will be safe and will improve the effectiveness of melanoma-specific T cells.